PROJECT SUMMARY/ABSTRACT_I_TH_______________________ Clare J. Lee, MD, is an Assistant Professor in the Division of Endocrinology, Diabetes and Metabolism at Johns Hopkins University. Dr. Lee seeks a Mentored Patient-Oriented Research Career Development Award in order to obtain the skills, knowledge and mentored research experience that are essential for an independent career as a physician scientist in the field of treatment and prevention of type 2 diabetes (T2DM). Bariatric surgery, especially vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB), is a highly effective treatment for T2DM, resulting in rapid and dramatic improvement in diabetes even before a significant weight loss. The mechanisms of glycemic improvement after bariatric surgery are incompletely understood. The objectives for this proposal are to study the extent to which gut hormones and gut microbiota relate to changes in glucose homeostasis after two bariatric surgeries, VSG and RYGB. The specific aims of the research agenda are to: 1) Compare changes in GIP, glucagon and glycemic variability after VSG versus RYGB, 2) Determine the extent to which changes in gut microbiota are linked with glycemic improvement after VSG and RYGB and the concurrent changes in the markers of gut translocation (e.g. LPS) and SCFA to understand the role of gut microbiota in host glucose homeostasis and to 3) Characterize and compare fasting and meal-stimulated insulin, glucagon, GLP-1 and GIP in patients with and without hypoglycemia after VSG versus RYGB. For Aims 1 and 2, we propose a prospective study in which we will enroll patients with T2DM undergoing VSG or RYGB and measure fasting and mixed-meal stimulated incretins and other hormones related to glucose metabolism and collect stool samples at three time points: baseline, 3 months or at 10% weight loss and 12 months post surgery. For Aim 3, we will enroll 40 individuals (post-VSG: 10 with and 10 without hypoglycemia, post-RYGB: 10 with and 10 without hypoglycemia) and measure fasting and mixed- meal stimulated incretins and other hormones. The goals during the award period include developing expertise in the design, performance, analysis and presentation of clinical research through mentored research, tailored didactic coursework, and supervised performance of relevant laboratory techniques. Long-term goals include developing a career as an independent clinical investigator and developing new approaches to treating and preventing T2DM. The proposed research aims to provide new insights to the contribution of gut hormones and gut microbiota to changes in glucose metabolism after bariatric surgery, thus laying the foundation to develop novel therapeutic targets for T2DM.